Throughout this application, technical and patent literature is identified by a citation or a first author and date of publication. Complete citations for the publications identified by author and date can be found in the application papers, immediately preceding the claims. The technical and patent literature are incorporated by reference into the specification to more fully describe the state of the art to which this invention pertains.
Chronic and recurrent infections result when the human body fails to clear the disease causing bacteria. One means by which bacteria persist is by invading human host cells. Once inside they are protected from the immune system and antimicrobial therapies. Moreover, these bacteria have evolved to divide and eventually kill these host cells, releasing the endogenous bacteria and allowing subsequent re-infection; this is the root cause of the chronicity of the disease state.
Many bacterial species multiply within organized communities as a part or whole of their lifestyles in the environment or in the host. Uropathogenic Escherichia coli (UPEC), the causative agent of up to 80% of all urinary tract infections (Foxman, B. (2010) Nat. Rev. Urol. 7:653-660), is one such species. UPEC uses a community-based developmental pathway to propagate within the cytoplasm of urothelial cells during bacterial cystitis (Justice, S. S. et al. (2004) Proc. Natl. Acad. Sci. U.S.A. 101:1333-1338; Mulvey, M. A. et al. (1998) Science 282:1494-1497; Anderson, G. G. et al. (2003) Science 301:105-107). The developmental pathway begins with attachment-mediated invasion into the superficial bladder epithelial cells via FimH binding to the mannosylated uroplakin proteins (Zhou, G. et al. (2002) Mol. Cell Proteomics 1:117-124) and involves fusiform vesicles (Bishop, B. L. et al. (2007) Nature Medicine 13, 625-630), cyclic AMP (Bishop, B. L. et al. (2007) Nature Medicine 13, 625-630), Toll-like receptor-4 (TLR4) (Song, J. et al. (2007) Cell Host Microbe 1:287-298) and integrins (Eto, D. S. et al. (2007) PLoS Pathog. 3:e100). Within the cytoplasm, bacillary-shaped UPEC multiply within loosely associated intracellular bacterial communities (IBCs) (Justice, S. S. et al. (2004) Proc. Natl. Acad. Sci. U.S.A. 101:1333-1338). IBC maturation involves both changes in cell division fidelity and community architecture, which results in coccoid-shaped UPEC in an organized, globular community architecture. Once the IBC occupies the majority of the cytoplasm, UPEC regain a bacillary shape, become motile and egress from the epithelial cell through disruptions in the cell membrane. The intracellular amplification of UPEC occurs in repetitive cycles through attachment of egressed organisms to naïve superficial epithelial cells and ultimately culminates in the establishment of a latent or chronic infection (Mulvey, M. A. et al. (2001) Infect. Immun. 69:4572-4579; Mysorekar, I. U. et al. (2006) Proc. Natl. Acad. Sci. U.S.A. 103:14170-14175; Hannan, T. J. et al. (2010) PLoS Pathog. 6(8):e1001042). Evidence for each of these stages is observed in urine samples and bladder biopsies of patients colonized with either UPEC or Klebsiella pneumoniae (Rosen, D. A. et al. (2007) PLoS Medicine 4:e329; Rosen, D. A. et al. (2008) Infect. Immun. 76:3337-3345), which demonstrates that these similar events comprise the pathogenic lifestyle of multiple uropathogens during cystitis.
This a need exists to stop or arrest infection of these pathogens. This invention satisfies this need and provides related advantages as well.